The transcription factor GATA6 accelerates vascular smooth muscle cell senescence-related arterial calcification by counteracting the role of anti-aging factor SIRT6 and impeding DNA damage repair.

Arterial calcification is a hallmark of vascular pathology in the elderly and in individuals with chronic kidney disease (CKD). Vascular smooth muscle cells (VSMCs), after attaining a senescent phenotype, are implicated in the calcifying process. However, the underlying mechanism remains to be elucidated. Here, we reveal an aberrant upregulation of transcriptional factor GATA6 in the calcified aortas of humans, mice with CKD and mice subjected to vitamin D3 injection. Knockdown of GATA6, via recombinant adeno-associated virus carrying GATA6 shRNA, inhibited the development of arterial calcification in mice with CKD. Further gain- and loss-of function experiments in vitro verified the contribution of GATA6 in osteogenic differentiation of VSMCs. Samples of human aorta exhibited a positive relationship between age and GATA6 expression and GATA6 was also elevated in the aortas of old as compared to young mice. Calcified aortas displayed senescent features with VSMCs undergoing premature senescence, blunted by GATA6 downregulation. Notably, abnormal induction of GATA6 in senescent and calcified aortas was rescued in Sirtuin 6 (SIRT6)-transgenic mice, a well-established longevity mouse model. Suppression of GATA6 accounted for the favorable effect of SIRT6 on VSMCs senescence prevention. Mechanistically, SIRT6 inhibited the transcription of GATA6 by deacetylation and increased degradation of transcription factor Nkx2.5. Moreover, GATA6 was induced by DNA damage stress during arterial calcification and subsequently impeded the Ataxia-telangiectasia mutated (ATM)-mediated DNA damage repair process, leading to accelerated VSMCs senescence and osteogenic differentiation. Thus, GATA6 is a novel regulator in VSMCs senescence. Our findings provide novel insight in arterial calcification and a potential new target for intervention.

Tetraspanin 1 regulates papillary thyroid tumor growth and metastasis through c-Myc-mediated glycolysis.

Papillary thyroid cancer (PTC) is the most common form of thyroid cancer and is characterized by its tendency for lymphatic metastasis, leading to a poor prognosis. Tetraspanin 1 (TSPAN1) is a member of the tetra-transmembrane protein superfamily and has been implicated in tumorigenesis and cancer metastasis in various studies. However, the role of TSPAN1 in PTC tumor development remains unclear. In this study, we aimed to investigate the impact of TSPAN1 on PTC cell behavior. Our results demonstrate that knockdown of TSPAN1 inhibits PTC cell proliferation, migration, and invasion, while overexpression of TSPAN1 has the opposite effect. These findings suggest that TSPAN1 might play a role in the tumorigenesis and invasiveness of PTC. Mechanistically, we found that TSPAN1 activates the ERK pathway by increasing its phosphorylation, subsequently leading to upregulated expression of c-Myc. Additionally, we observed that TSPAN1-ERK-c-Myc axis activation promotes glycolytic activity in PTC cells, as evidenced by the upregulation of glycolytic genes such as LDHA. Taken together, our findings indicate that TSPAN1 acts as an oncogene in PTC by regulating glycolytic metabolism. This discovery highlights the potential of TSPAN1 as a promising therapeutic target for PTC treatment. Further research in this area could provide valuable insights into the development of targeted therapies for PTC patients.

Efficacy and safety of preoperative transarterial chemoembolization for hepatocellular carcinoma: a systematic review and meta-analysis.

OBJECTIVE: The aim of the study was to compare preoperative transcatheter arterial chemotherapy (TACE) plus liver resection (LR) with liver resection (LR) alone for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: PubMed, Embase, Cochrane library, web of science and China National Knowledge Infrastructure (CNKI) were searched from their initiation until 24 August 2021. Eligible languages were English and Chinese. This study includes only RCT and cohort studies. The primary outcome was the prognostic factors including overall survival rate (OS), disease-free survival (DFS), recurrence-free survival (RFS), and we also research the operative time, intraoperative blood loss, and postoperative complication. RESULTS: Twenty-nine trials (2 RCTs and 27 cohorts) were included, containing a total of 22023 patients, compared with hepatic resection, preoperative TACE plus LR shows the benefit of RFS (Hazard Ratio (HR)=0.80, 95%CI = [0.73-0.88], p < .001), and the combined therapy was associated with a higher OS for patients with HCC in Barcelona Clinic Liver Cancer (BCLC) B stage (HR = 0.76, 95%CI = [0.60-0.96], p = .024). In terms of safety, combination therapy is related to less intraoperative blood loss (Weighted Mean Difference (WMD)=-11.17, 95%CI = [-21.79 to -0.54], p = .039); and there's no statistical significance in postoperative complication (Risk Ratio (RR)=0.99, 95%CI= [0.90-1.08], p = 0.771) and operative time (WMD = 7.57, 95%CI = [-5.07 to 20.20], p = .240). CONCLUSION: TACE prior to surgery should be recommended as a routine treatment for HCC patients, especially BCLC B stage HCC, in view of its benefits for RFS and OS. Large, multicenter, and blinded randomized trials should be performed to confirm these findings.

Role of gut microbiota-derived metabolites on vascular calcification in CKD.

The interaction between gut microbiota and the host has gained widespread concern. Gut microbiota not only provides nutrients from the ingested food but also generates bioactive metabolites and signalling molecules to impact host physiology, especially in chronic kidney disease (CKD). The development of CKD, accompanied by changed diet and medication, alters the gut flora and causes the effect in distant organs, leading to clinical complications. Vascular calcification (VC) is an actively regulated process and a high prevalence of VC in CKD has also been linked to an imbalance in gut microbiota and altered metabolites. In this review, we focused on gut microbiota-derived metabolites involved in VC in CKD and explained how these metabolites influence the calcification process. Correcting the imbalance of gut microbiota and regulating microbiota-derived metabolites by dietary modification and probiotics are new targets for the improvement of the gut-kidney axis, which indicate innovative treatment options of VC in CKD.

Aldosterone enhances high phosphate-induced vascular calcification through inhibition of AMPK-mediated autophagy.

It remains unclear whether the necessity of calcified mellitus induced by high inorganic phosphate (Pi) is required and the roles of autophagy plays in aldosterone (Aldo)-enhanced vascular calcification (VC) and vascular smooth muscle cell (VSMC) osteogenic differentiation. In the present study, we found that Aldo enhanced VC both in vivo and in vitro only in the presence of high Pi, alongside with increased expression of VSMC osteogenic proteins (BMP2, Runx2 and OCN) and decreased expression of VSMC contractile proteins (α-SMA, SM22α and smoothelin). However, these effects were blocked by mineralocorticoid receptor inhibitor, spironolactone. In addition, the stimulatory effects of Aldo on VSMC calcification were further accelerated by the autophagy inhibitor, 3-MA, and were counteracted by the autophagy inducer, rapamycin. Moreover, inhibiting adenosine monophosphate-activated protein kinase (AMPK) by Compound C attenuated Aldo/MR-enhanced VC. These results suggested that Aldo facilitates high Pi-induced VSMC osteogenic phenotypic switch and calcification through MR-mediated signalling pathways that involve AMPK-dependent autophagy, which provided new insights into Aldo excess-associated VC in various settings.

Development and validation of a preoperative prediction model for follicular thyroid carcinoma.

OBJECTIVE: The low pre- and intraoperative diagnostic rates in follicular thyroid carcinoma (FTC) often lead to inadequate surgical resection and necessitate further completion surgery. Therefore, the preoperative prediction of FTC in thyroid nodules is essential. DESIGN AND PATIENT: Patients were categorized into two data sets: the modelling data set, which included 3649 patients admitted to our centre between January 2014 and December 2016, and the validation data set, which included 1253 patients admitted between January and December 2017. Patient data from the FTC and non-FTC groups were initially included in a modelling data set to establish a preoperative prediction model. This model was subsequently employed in a validation data set for external validation of the predictive value. The positivity rate for FTC predicted by the model was compared with that of the intraoperative frozen sections. RESULTS: The preoperative serum thyroglobulin level, nodule diameter, calcification status, solidity and blood supply were selected as predictors for the model. The regression equation was as follows: Y = 0.010 × (thyroglobulin level) + 0.556 × (nodule diameter) + 0.675 × (calcification status) + 2.355 × (nodule component) + 1.072*(blood flow) - 9.787. The model positively predicted FTC at values of Y ≥ -4.11. The accuracy, sensitivity, specificity, positive likelihood ratio and negative likelihood ratio of the prediction model were 89.2%, 90.2%, 87.7%, 39.2 and 0.11, respectively. External validation of the model demonstrated acceptable results. The positive prediction rate of the model was 90.7% (78/86), which was significantly higher than that of the intraoperative frozen sections (10.5% [9/86]; P < 0.0001). CONCLUSIONS: We successfully established and validated a simple and reliable preoperative prediction model for FTC using the preoperative thyroglobulin level and ultrasonographic features of the thyroid nodules. This model may improve the preoperative evaluation of FTC in clinical settings and facilitate the development of a reasonable surgical programme for FTC.

Application of Continuous and Intermittent Intraoperative Nerve Monitoring in Thyroid Surgery.

BACKGROUND: Whether continuous intraoperative nerve monitoring (C-IONM) can further reduce the incidence of recurrent laryngeal nerve injury compared with intermittent intraoperative nerve monitoring (I-IONM) in high-risk thyroid surgery is still controversial. This observational study aimed to evaluate the incidence of vocal cord paralysis (VCP) in high-risk thyroid surgeries performed with I-IONM and C-IONM. MATERIALS AND METHODS: High-risk thyroid surgical patients operated with I-IONM or C-IONM by the same group of surgeons in the thyroid surgery department of our institution between January 2014 and February 2018 were analyzed. Differences in the incidence rates of temporary and permanent VCP between the two groups were compared. A P-value < 0.05 was considered statistically significant. RESULTS: A total of 344 patients who underwent high-risk thyroid surgery (550 nerves at risk [NARs]) were observed, with 238 patients (374 NARs) operated with I-IONM and 106 patients (173 NARs) operated with C-IONM. The incidence of temporary and permanent VCP was 1.9% (7/374) and 0.8% (3/374) in the I-IONM group and 1.2% (2/173) and 0% (0/173) in the C-IONM group, respectively, showing no statistical difference (P = 0.726 and P = 0.555). The incidence rate of impending recurrent laryngeal nerve injuries successfully prevented in the C-IONM group was 5.2% (9/173). CONCLUSIONS: Both I-IONM and C-IONM are equally safe and effective in high-risk thyroid surgery. C-IONM can help predict impending recurrent laryngeal nerve injury in real time and has a good warning feature, thereby minimizing critical maneuvers in high-risk thyroid surgery.

N-myc downstream-regulated gene 2 inhibits human cholangiocarcinoma progression and is regulated by leukemia inhibitory factor/MicroRNA-181c negative feedback pathway.

Increasing evidence supports a role for N-myc downstream-regulated gene 2 (NDRG2) deregulation in tumorigenesis. We investigated the roles and mechanisms of NDRG2 in human cholangiocarcinoma (CCA) progression. In the present study, expression of NDRG2, microRNA (miR)-181c and leukemia inhibitory factor (LIF) in human CCA and adjacent nontumor tissues were examined. The effects of NDRG2 on CCA tumor growth and metastasis were determined both in vivo and in vitro. The role of the NDRG2/LIF/miR-181c signaling pathway in cholangiocarcinogenesis and metastasis were investigated both in vivo and in vitro. The results showed that human CCA tissues exhibited decreased levels of NDRG2 and increased levels of miR-181c and LIF compared with nontumor tissues. NDRG2 could inhibit CCA cell proliferation, chemoresistance, and metastasis both in vitro and in vivo. We found that NDRG2 is a target gene of miR-181c, and the down-regulation of NDRG2 was attributed to miR-181c overexpression in CCA. Furthermore, miR-181c can be activated by LIF treatment, whereas NDRG2 could inhibit LIF transcription through disrupting the binding between Smad, small mothers against decapentaplegic complex and LIF promoter. Down-regulation of NDRG2 and overexpression of miR-181c or LIF are significantly associated with a poorer overall survival (OS) in CCA patients. Finally, we found that a combination of NDRG2, miR-181c, and LIF expression is a strong predictor of prognosis in CCA patients. CONCLUSION: These results establish the counteraction between NDRG2 and LIF/miR-181c as a key mechanism that regulates cholangiocarcinogenesis and metastasis. Our results elucidated a novel pathway in NDRG2-mediated inhibition of cholangiocarcinogenesis and metastasis and suggest new therapeutic targets, including NDRG2, LIF, miR-181c, and transforming growth factor beta, in CCA prevention and treatment. (Hepatology 2016;64:1606-1622).

Reciprocal activation between ATPase inhibitory factor 1 and NF-κB drives hepatocellular carcinoma angiogenesis and metastasis.

UNLABELLED: Hepatocellular carcinoma (HCC) is a highly vascularized tumor with frequent extrahepatic metastasis. Active angiogenesis and metastasis are responsible for rapid recurrence and poor survival of HCC. However, the mechanisms that contribute to tumor metastasis remain unclear. Here we evaluate the effects of ATPase inhibitory factor 1 (IF1), an inhibitor of the mitochondrial H(+)-adenosine triphosphate (ATP) synthase, on HCC angiogenesis and metastasis. We found that increased expression of IF1 in human HCC predicts poor survival and disease recurrence after surgery. Patients with HCC who have large tumors, with vascular invasion and metastasis, expressed high levels of IF1. Invasive tumors overexpressing IF1 were featured by active epithelial-mesenchymal transition (EMT) and increased angiogenesis, whereas silencing IF1 expression attenuated EMT and invasion of HCC cells. Mechanistically, IF1 promoted Snai1 and vascular endothelial growth factor (VEGF) expression by way of activating nuclear factor kappa B (NF-κB) signaling, which depended on the binding of tumor necrosis factor (TNF) receptor-associated factor 1 (TRAF1) to NF-κB-inducing kinase (NIK) and the disruption of NIK association with the TRAF2-cIAP2 complex. Suppression of the NF-κB pathway interfered with IF1-mediated EMT and invasion. Chromatin immunoprecipitation assay showed that NF-κB can bind to the Snai1 promoter and trigger its transcription. IF1 was directly transcribed by NF-κB, thus forming a positive feedback signaling loop. There was a significant correlation between IF1 expression and pp65 levels in a cohort of HCC biopsies, and the combination of these two parameters was a more powerful predictor of poor prognosis. CONCLUSION: IF1 promotes HCC angiogenesis and metastasis by up-regulation of Snai1 and VEGF transcription, thereby providing new insight into HCC progression and IF1 function. (Hepatology 2014;60:1659-1673).

Gankyrin promotes tumor growth and metastasis through activation of IL-6/STAT3 signaling in human cholangiocarcinoma.

UNLABELLED: Although gankyrin is involved in the tumorigenicity and metastasis of some malignancies, the role of gankyrin in cholangiocarcinoma (CCA) is unclear. In this study we investigated the expression of gankyrin in human CCA tissues and cell lines. The effects of gankyrin on CCA tumor growth and metastasis were determined both in vivo and in vitro. The results showed that gankyrin was overexpressed in CCA tissues and cell lines. Gankyrin expression was associated with CCA histological differentiation, TNM stage, and metastasis. The multivariate Cox analysis revealed that gankyrin was an independent prognostic indicator for overall survival. Gankyrin overexpression promoted CCA cell proliferation, migration, and invasion, while gankyrin knockdown inhibited CCA tumor growth, metastasis, and induced Rb-dependent senescence and G1 phase cell cycle arrest. Gankyrin increased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and promoted the nuclear translocation of p-STAT3. Suppression of STAT3 signaling by small interfering RNA (siRNA) or STAT3 inhibitor interfered with gankyrin-mediated carcinogenesis and metastasis, while interleukin (IL)-6, a known upstream activator of STAT3, could restore the proliferation and migration of gankyrin-silenced CCA cells. The IL-6 level was decreased by gankyrin knockdown, while increased by gankyrin overexpression. Gankyrin regulated IL-6 expression by way of facilitating the phosphorylation of Rb; meanwhile, rIL-6 treatment increased the expression of gankyrin, suggesting that IL-6 was regulated by a positive feedback loop involving gankyrin in CCA. In the xenograft experiments, gankyrin overexpression accelerated tumor formation and increased tumor weight, whereas gankyrin knockdown showed the opposite effects. The in vivo spontaneous metastasis assay revealed that gankyrin promoted CCA metastasis through IL-6/STAT3 signaling pathway. CONCLUSION: Gankyrin is crucial for CCA carcinogenesis and metastasis by activating IL-6/STAT3 signaling pathway through down-regulating Rb protein.

Paraoxonase 2 gene polymorphisms and prenatal phthalates' exposure in Chinese newborns.

BACKGROUND: Phthalates were reported to be associated with increased risk of LBW in newborns, but the mechanism and potential influencing factor was still unclear. The objectives of this study were to investigate whether paraoxonase-2 (PON2) Ala148Gly (A148G) polymorphisms have impacts on fetal growth, and evaluate potential modifying effect on the association between phthalate exposures and LBW and short birth length. METHODS: In the current case-control study, 185 mother-newborn pairs including 74 low birth weight (LBW) cases and 111 controls were enrolled. Newborns' meconium specimens were collected and detected for mono-n-butyl phthalate (MBP) and mono-2-ethyhexyl phthalate (MEHP) by the method of high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Umbilical vein blood samples were used to identify PON2 A148G polymorphisms by using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: Newborns prenatally exposed to higher level of phthalates had lower birth weight (ß=-0.92. p=0.045 for MBP, ß=-0.62, p=0.013 for MEHP) and short birth length (SBL) (ß=-0.024. p=0.049 for MBP, ß=-0.023, p=0.007 for MEHP). Comparing with low-phthalate-exposed subjects with PON2 148AA genotype, newborns with PON2 148AG/GG genotype exposed to high concentrations of MBP and MEHP had higher risks of LBW and short birth length (LBW: OR: 5.0, p=0.017 for MEHP; OR: 2.6, p=0.023 for MBP; SBL: OR: 6.6, p=0.005 for MEHP; OR: 6.4, p=0.017 for MBP). Effects of MBP and MEHP on LBW were significantly modified by PON2 A148G (p=0.044 and 0.034, respectively), while the modifying effect of PON2 A148G polymorphisms on the association of two phthalate metabolites with SBL was not significant. CONCLUSION: Prenatal exposure to phthalates affected birth weight and length in newborns. PON2 A148G polymorphisms modified the effects of prenatal phthalates' exposure on fetal development. Newborns with PON2 148AG/GG genotype and exposed to high concentrations of MBP and MEHP had higher risks of LBW and SBL.

Nutlin-3 overcomes arsenic trioxide resistance and tumor metastasis mediated by mutant p53 in Hepatocellular Carcinoma.

BACKGROUND: Arsenic trioxide has been demonstrated as an effective anti-cancer drug against leukemia and solid tumors both in vitro and in vivo. However, recent phase II trials demonstrated that single agent arsenic trioxide was poorly effective against hepatocellular carcinoma (HCC), which might be due to drug resistance. METHODS: Mutation detection of p53 gene in arsenic trioxide resistant HCC cell lines was performed. The therapeutic effects of arsenic trioxide and Nutlin-3 on HCC were evaluated both in vitro and in vivo. A series of experiments including MTT, apoptosis assays, co-Immunoprecipitation, siRNA transfection, lentiviral infection, cell migration, invasion, and epithelial-mesenchy-mal transition (EMT) assays were performed to investigate the underlying mechanisms. RESULTS: The acquisition of p53 mutation contributed to arsenic trioxide resistance and enhanced metastatic potential of HCC cells. Mutant p53 (Mutp53) silence could re-sensitize HCC resistant cells to arsenic trioxide and inhibit the metastatic activities, while mutp53 overexpression showed the opposite effects. Neither arsenic trioxide nor Nutlin-3 could exhibit obvious effects against arsenic trioxide resistant HCC cells, while combination of them showed significant effects. Nutlin-3 can not only increase the intracellular arsenicals through inhibition of p-gp but also promote the p73 activation and mutp53 degradation mediated by arsenic trioxide. In vivo experiments indicated that Nutlin-3 can potentiate the antitumor activities of arsenic trioxide in an orthotopic hepatic tumor model and inhibit the metastasis to lung. CONCLUSIONS: Acquisitions of p53 mutations contributed to the resistance of HCC to arsenic trioxide. Nutlin-3 could overcome arsenic trioxide resistance and inhibit tumor metastasis through p73 activation and promoting mutant p53 degradation mediated by arsenic trioxide.

Gender-specific relationship between prenatal exposure to phthalates and intrauterine growth restriction.

BACKGROUND: No study has examined the association between prenatal phthalate exposure and intrauterine growth retardation (IUGR). This study aimed to investigate whether prenatal exposure to phthalates was associated with increased risk of IUGR. METHODS: A total of 126 mother-newborn pairs, including 42 IUGR cases and 84 control newborns and their mothers, were enrolled in this case-control study. Spot urine samples were collected during the third trimester of pregnancy, and 5 phthalate metabolites (mono-n-butyl phthalate (MBP), monomethyl phthalate (MMP), mono-2-ethylhexyl phthalate (MEHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP)) were measured. RESULTS: Concentrations of MMP, MEHHP, MEOHP, and SumDEHP (MEHP, MEHHP, and MEOHP) were significantly higher in IUGR cases than in normal controls. In all subjects, urinary concentrations of MEHHP and MEOHP were significantly inversely associated with fetal growth indicators (birth weight and Quetelet's index). When mothers were stratified by infant sex, MEHHP and MEOHP concentrations were still negatively associated with fetal growth indicators, while no significant association was observed in females. In addition, exposure-response relationships were observed between MEHHP/SumDEHP concentrations in maternal urine and IUGR. CONCLUSION: Prenatal exposure to phthalates was associated with increased risk of IUGR, and male newborns were more sensitive to phthalates than females.

[11beta-hydroxysteroid dehydrogenase type 2 enzyme activity effect after exposures phthalate esters in maternal].

OBJECTIVE: To study the association between phthalate esters (PAEs) metabolites in maternal urine and 11beta-hydroxysteroid dehydrogenase type 2 (11ß-HSD2 ) enzyme activity, explore the possible mechanism of PAEs effect on fetal development. METHODS: All of 33 cases of intrauterine growth retardation (IUGR) newborn were selected by random sampling in 2012. And 33 cases of normal control newborn were enrolled, use high performance liquid chromatography-tandem mass spectrometry method was used to detect 4 kinds of phthalate esters (PAEs) metabolites in maternal urine: mono-n-butyl phthalate ester (MBP), mono (2-ethylhexyl) phthalate (MEHP), mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono (2-ethyl-5-oxohexyl) phthalate (MEOHP) and three kinds of cortisol corticosterone metabolites, tetrahydrocortisol (THF), allo-tetrahydrocortisol (allo-THF), tetrahydrocortisone (THE), and analyze the association between phthalate esters (PAEs) metabolites in maternal urine and 11ß-HSD2 enzyme activity. RESULTS: MBP, MEHP, MEHHP, MEOHP metabolites can be detected in 98% (65 cases) , 89% (59 cases), 91% (60 cases), 91% (60 cases) of all 66 maternal urine samples, respectively. The median concentrations of test material in case group were 31.20 ng/ml for MBP, 24.61 ng/ml for MEHHP, 11.72 ng/ml for MEOHP and 48.67 ng/ml for SumDEHP which were significantly higher than those of the control group (were 17.32, 12.03, 5.68 and 28.64 ng/ml); 11ß-HSD2 activity in case group ((THF+allo-THF)/THE = (0.79 ± 0.09) ng/ml) was significantly lower than that of the control group((THF+allo-THF)/THE = (0.58 ± 0.04) ng/ml); PAEs metabolites MBP (ß' = 1.12), MEHHP(ß' = 1.14), MEOHP(ß' = 1.10), SumDEHP(ß' = 1.08) in baby boy mother's urine was reversely correlated to 11ß-HSD2 activity. CONCLUSIONS: PAEs could affect fetal development by inhibit 11ß-HSD2 activity.

Ten-year trajectory of coronary artery calcification and risk of cardiovascular outcomes: the Multi-Ethnic Study of Atherosclerosis.

Background: Whether and how coronary artery calcium (CAC) progress contributes to cardiovascular outcomes has not been fully elucidated. The aim of this study was to identify different patterns of CAC change and evaluate the associations with different cardiovascular outcomes. Methods: Data from the Multi-Ethnic Study of Atherosclerosis study were analyzed. Participants with at least three CT measurements were included. The main study outcome is hard cardiovascular disease (CVD). CAC scores were determined as phantom-adjusted Agatston scores. A group-based trajectory model was used to identify latent groups and estimated the hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional regression models. Results: A total of 3,616 participants were finally enrolled [mean age 60.55 (SD 9.54) years, 47.76% men and 39.30% Caucasian]. Four distinct trajectories in CAC were identified: class 1, low-stable (24.17%); class 2, low-increasing (27.60%); class 3, moderate-increasing (30.56%); and class 4, elevated-increasing (17.67%). During 13.58 (SD 2.25) years of follow-up, 291 cases of hard CVD occurred. The event rates of hard CVD per 1,000 person-years were 2.23 (95% CI 1.53-3.25), 4.60 (95% CI 3.60-5.89), 7.67 (95% CI 6.38-9.21) and 10.37 (95% CI 8.41-12.80) for classes 1-4, respectively. Compared to participants assigned to class 1, the full-adjusted HRs of hard CVD for classes 2-4 were 2.10 (95% CI 1.33-3.01), 3.17 (95% CI 2.07-4.87), and 4.30 (95% CI 2.73-6.78), respectively. The graded positive associations with hard CVD were consistently observed in subgroups of age, sex, and race, with the presence or absence of hypertension or diabetes. By analyzing potential risk factors for distinctive CAC trajectories, risk factors for the onset and progression of CAC could possibly differ: age, male sex, history of hypertension, and diabetes are consistently associated with the low-, moderate-, and elevated-increasing trajectories. However, Caucasian race, cigarette smoking, and a higher body mass index was related only to risk of progression but not to incident CAC. Conclusion: In this multi-ethnic population-based cohort, four unique trajectories in CAC change over a 10-year span were identified. These findings signal an underlying high-risk population and may inspire future studies on risk management.

[Effect of docosahexaenoic acid and nervonic acid on the damage of learning and memory abilities in rats induced by 1-bromopropane].

OBJECTIVE: To investigate the protective effects of docosahexaenoic acid (DHA) and nervonic acid (NA) on the learning and memory abilities in rats exposed to 1-bromopropane (1-BP) and their action mechanisms. METHODS: Forty male Wistar rats (specific pathogen-free) were randomly divided into 4 groups (n = 10 for each), i.e., solvent control group, 1-BP (800 mg/kg) group, NA (150 mg/kg) + 1-BP (800 mg/kg) group, and DHA (500 mg/kg) + 1-BP (800 mg/kg) group. The rats were given respective test substances by gavage for 7 d. The Morris water maze (MWM) test was performed from days 8 to 12 to evaluate the rats' learning and memory abilities. After MWM test, rats were sacrificed in the next day, and cerebral cortex was quickly dissected and homogenized in an ice bath. The supernatant of the obtained homogenate was collected to measure the content of glutathione (GSH) and malondialdehyde (MDA) and the activities of glutathione reductase (GR) and γ-glutamate cysteine ligase (γ-GCL). RESULTS: The MWM spatial navigation test showed that the 1-BP group had significantly longer escape latency and significantly longer total swimming distance compared with the control group (P<0.05), while the DHA+1-BP group had significant decreases in escape latency and total swimming distance compared with the 1-BP group (P<0.05). The spatial probe test showed that the number of platform crossings was significantly greater in the DHA+1-BP group and NA+1-BP group than in the 1-BP group (P<0.05); compared with the control group, the 1-BP group had a significantly lower ratio of time spent in the zone around the platform to total time (P < 0.05), and the ratio was significantly higher in the DHA+1-BP group than in the 1-BP group (P < 0.05). Compared with the control group, the 1-BP group had a 18.1% decrease in GSH content, and DHA could significantly reverse 1-BP-induced decrease in GSH content (P < 0.05). Compared with the 1-BP group, the DHA+1-BP group and NA+1-BP group had significantly decreased MDA content (P < 0.05), the DHA+1-BP group had significantly increased GR activity (P < 0.05), and the NA+1-BP group had significantly increased γ-GCL activity (P < 0.05). CONCLUSION: The rats exposed to 1-BP have oxidative stress in the brain and impaired cognitive function. DHA and NA can reduce 1-BP-induced cognitive function impairment in rats, possibly by increasing the activities of GR and γ-GCL and the content of GSH in the brain.

Burden, Trends, and Inequalities of Heart Failure Globally, 1990 to 2019: A Secondary Analysis Based on the Global Burden of Disease 2019 Study.

Background Heart failure is a public health issue worldwide. However, no comprehensive study on the global burden of heart failure and its contributing causes has been reported. The present study aimed to quantify the burden, trends, and inequalities of heart failure globally. Methods and Results Heart failure data were extracted from the Global Burden of Diseases 2019 study. The number of cases, age-standardized prevalence, and years lived with disability in different locations from 1990 to 2019 were presented and compared. Joinpoint regression analysis was performed to assess trends in heart failure from 1990 to 2019. In 2019, the global age-standardized prevalence and years lived with disability rates for heart failure were 711.90 (95% uncertainty interval [UI], 591.15-858.29) and 63.92 (95% UI, 41.49-91.95) per 100 000 population, respectively. In general, the age-standardized rate decreased globally at an average annual percentage change of 0.3% (95% UI, 0.2-0.3). However, the rate increased at an average annual percentage change of 0.6% (95% UI, 0.4-0.8) from 2017 to 2019. Several nations and territories demonstrated an increased trend from 1990 to 2019, especially in less-developed countries. Ischemic heart disease and hypertensive heart disease accounted for the highest proportion of heart failure in 2019. Conclusions Heart failure remains a major health problem, with increased trends possible in the future. Efforts for prevention and control of heart failure should focus more on less-developed regions. It is essential to prevent and treat primary diseases such as ischemic heart disease and hypertensive heart disease for the control of heart failure.

Dental Diseases Increase Risk of Aortic Arch Calcification Independent of Renal Dysfunction in Older Adults: Shenzhen Community Cohort Study.

Many studies have documented that dental diseases were associated with an increased risk of cardiovascular diseases. Aortic arch calcification (AoAC) is a powerful predictor of cardiovascular diseases. However, whether the status of dental health is associated with AoAC is still unknown. 9463 participants over the age of 60 from Shenzhen community centers were included in the cross-sectional analysis. Physical examination data, blood biochemical tests, and AoAC scores calculated by chest radiography were collected and analyzed. Among them, 2630 participants were followed up for AoAC progression up to 36 months. Participants with AoAC suffered more tooth loss than those without AoAC (77.62% vs. 72.91%; p < 0.001). Association rule analysis suggested a strong association between dental diseases and AoAC. Tooth loss or decay increased the risk of AoAC progression (HR 1.459; 95%CI 1.284−1.658) after adjusting other risk factors including renal dysfunction. Dental diseases are potential predictors for AoAC in elderly people, which are independent of renal dysfunction.

Dissecting the Association of Genetically Predicted Neuroticism with Coronary Artery Disease: A Two-Sample Mendelian Randomization Study.

BACKGROUND: Observational studies on the association between neuroticism and coronary artery disease (CAD) are still rare, and the results of existing studies are not consistent. The present study aimed to explore causal associations of neuroticism with CAD. METHODS: The summary-level data of GWAS for neuroticism and 12 items used to assess neuroticism were extracted from the UK Biobank, and included up to 380,506 participants. The general data for CAD were obtained from the CARDIoGRAMplusC4D consortium, which assembled 60,801 CAD patients and 123,504 non-cases. Single-nucleotide polymorphisms associated with neuroticism and 12 items at genome-wide significance were explored as instrumental variables. Two-sample Mendelian randomization (TSMR) analyses were performed to evaluate causal associations amongst the genetically predicted neuroticism and 12 items with CAD. RESULTS: The present TSMR study did not reveal the genetic association of neuroticism with CAD. The calculated ORs for CAD using inverse-variance weighted, weighted median, and MR-Egger analysis were 1.12 (p-value = 0.187), 0.99 (p-value = 0.943), and 0.82 (p-value = 0.683), respectively. Further TSMR analysis of 12 dichotomous items for assessing neuroticism suggested that mood swings genetically increased the risk of CAD (OR = 1.67, p-value < 0.001). CONCLUSIONS: This study reported no genetically causal association of neuroticism with CAD. The present study also found that mood swings may genetically increase the risk of CAD. These findings may highlight the potential of mood control as a preventive measure for CAD.